Haematological malignancies Cancer
Conditions
Interventions
The dose escalation phase (Phase I) will consist of two parts. In Part I, NVG-222 will be administered in single participant cohorts. These participants will follow accelerated dose escalation with in
Phase IIa), participants will receive NVG-222 as an intravenous infusion at a dose and schedule that will be determined based on data from the dose escalation phase.
All participants may receive NVG-
Sponsors
Cancer Research UK
Eligibility
Sex/Gender
All
Age
18 Years to 100 Years
Inclusion criteria
Inclusion criteria: 1. Written (signed and dated) informed consent and be capable of co-operating with Investigational Medicinal Product (IMP) administration and follow-up. 2. All patients must have relapsed or have refractory disease. Patients must have received at least two prior lines of treatment including, as appropriate, high-dose chemoimmunotherapy, CAR T-cell therapy, CD20 bispecific antibody therapy, haemopoietic stem cell transplant, targeted therapies including BTKi and BCL2 inhibitors. Approved therapies should have been received unless these therapies are contraindicated, intolerable to the patient, or declined by the patient. Histologic documentation of disease and/or flow cytometry of disease: Patients with documented diagnosis for one of the following B-cell malignancies anticipated to express ROR1 according to the World Health Organization Classification of Haematolymphoid Tumours, 5th Edition (WHO-HAEM5) and requiring treatment: 2.1. Chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL) 2.2. Richter’s 2.3. Large B-cell lymphoma (LBCL; including all subtypes and high-grade B cell not otherwise specified) 2.4. Burkitt lymphoma 2.5. Follicular lymphoma (FL; including all sub-types) 2.6. Marginal zone lymphoma (MZL; extranodal and nodal) 2.7. Splenic B-cell lymphomas and leukaemias 2.8. Mantle cell lymphoma (MCL) 2.9. Lymphoplasmacytic lymphoma, including Waldenström macroglobulinaemia (WM) 2.10. Transformed indolent NHL (iNHL) 3. Objectively evaluable or measurable disease, defined by the appropriate disease response criteria as follows: 3.1. iwCLL for participants with CLL/SLL, 3.2. IWWM-6 for participants with WM 3.3. Lugano classification for participants with LBCL, MCL, MZL, splenic B-cell lymphomas and leukaemias, Burkitt lymphoma, lymphoplastic lymphoma (excluding WM), transformed iNHL, and FL 4. Life expectancy of at least 12 weeks. 5. Eastern Cooperative Oncology Group performance status of 0–1. 6. Haematological and biochemical indices within prescribed ranges. 7. Aged 18 years or over at the time consent is given.
Exclusion criteria
Exclusion criteria: 1. Patient has received any of the following: 1.1. Radiotherapy (except for palliative reasons), chemotherapy or other IMPs during the previous 4 weeks before first dose of IMP (or last dose of an immunotherapy during the previous 4 weeks). 1.2. Therapeutic antibodies (for any indication), within 4 weeks prior to first NVG-222 administration. 1.3. Prior treatment with CAR-T therapy within 4 weeks prior to first NVG-222 administration. 1.4. Autologous haematopoeitic stem cell transplantation (HSCT) within 100 days prior to first NVG-222 administration, or solid organ transplantation. 1.5. Allogeneic HSCT or donor lymphocyte infusion within 6 months prior to first NVG-222 administration. 2. Ongoing toxic manifestations of previous treatments greater than CTCAE Grade 1 with certain exceptions permitted as per protocol. 3. Active central nervous system (CNS) involvement. Primary CNS lymphoma, CNS involvement by lymphoma at screening, CNS metastasis that requires treatment or leptomeningeal involvement of the tumour under study with certain exceptions permitted as per protocol. 4. History or presence of dementia, or psychosis with certain exceptions permitted as per protocol. 5. Women who are pregnant or breastfeeding (or planning to breastfeed). 6. Women of childbearing potential. However, those patients who are not pregnant or breastfeeding are eligible provided they have a negative highly sensitive serum pregnancy test within 7 days before enrolment and agree to follow the trial’s contraceptive requirements. 7. Male patients with partners of childbearing potential. However, those patients who agree to follow the trial’s contraceptive guidance are eligible. 8. Any major surgery from which the patient has not yet recovered (excluding biopsy collection if applicable). 9. Active uncontrolled infection. 10. Uncontrolled autoimmune haemolytic anaemia or idiopathic thrombocytopenic purpura within 8 weeks of Screening. 11. Patient is unable to receive at least one of the following prophylactic medications for tumour lysis syndrome: allopurinol, febuxostat or rasburicase. 12. Patients with history of significant AEs related to prior immunotherapies. 13. The use of corticosteroids treatment =10 mg/day prednisone or equivalent is permitted; however, there must be documentation that the patient was on a stable dose of at least 14 days duration prior to trial enrolment. Inhaled and topical steroids are permitted. 14. Known to be serologically positive for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). 14.1. Active hepatitis B infection. Patients with negative serologic or PCR test results for acute or chronic HBV infection are eligible. 14.2. Active hepatitis C infection. Patients who test positive for hepatitis C antibody with a detectable HCV load are not eligible. 14.3. Patients with known HIV are excluded unless viral load is undetectable and CD4 count is above 300 cells/mm3 on stable Highly Active Antiretroviral Therapy. 15. Known or suspected hypersensitivity reaction to previous biological therapy or any of the NVG-222 excipients that, in the opinion of the Investigator, is a contraindication for participation in this trial. 16. Significant cardiovascular disease as defined within the protocol. 17. Clinically significant lung disease as defined within the protocol. 18. Participating in or plans to participate in another interventional clinical trial whilst taking part in this Phase I/IIa trial of NVG-
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1. Nature and frequency of dose-limiting toxicities (DLTs). DLTs are defined and assessed according to specific criteria in the trial protocol. Evaluation of this endpoint will occur when sufficient participants have completed the DLT assessment period (first 28 days of administration) and all relevant data have been collected. 2. Determination of the maximum tolerated dose (MTD) and/or optimal biological dose (OBD) and/or therapeutic dose range and/or optimal dose schedule for NVG-222. The Bayesian optimal interval model will recommend the NVG-222 dose with an estimated DLT rate within the target range of 20% to 33%. In the absence of DLT, the single agent recommended Phase II dose or OBD and schedule will be determined based upon the maximum administered dose and all available safety, pharmacokinetic (PK) and pharmacodynamic data. Evaluation of this endpoint will occur when sufficient participants have completed the DLT assessment period (first 28 days of administration) and all clinically relevant data have been reviewed by the Sponsor, Chief Investigator and Principal Investigators. 3. Frequency of adverse events (AEs) considered at least possibly related to NVG-222 and number of Grade 3, 4 and 5 AEs considered at least possibly related to NVG-222 over the first 12 months of dosing. AEs, including relatedness, seriousness and severity (graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 5.0 with the exception of cytokine release syndrome [CRS] and neurotoxicity [ICANS], which will be graded according to American Society for Transplantation and Cellular Therapy [ASTCT] consensus grading) will be assessed by the Investigator. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. PK parameters of NVG-222, including minimum concentration (Cmin), maximum concentration (Cmax), area under the curve (AUC), clearance (CL), volume of distribution (Vd) and terminal elimination half-life (t1/2), in blood (serum) for intravenous administration, measured using a standard ligand binding assay. Additional PK parameters may be determined as appropriate. Samples for PK analysis will be taken at up to 30 timepoints for each participant over the duration of the trial. 2. Objective response rate, defined as the proportion of participants who achieve complete response (CR), partial response (PR)/partial remission as the best overall response according to disease-specific assessment criteria. This endpoint will be evaluated at 12 months and the end of trial (EoT). 3. Complete response rate, defined as the proportion of participants with a best overall response of CR according to disease-specific assessment criteria. This endpoint will be evaluated at 12 months and EoT. 4. Disease control rate, defined as the percentage of participants who achieve CR, PR/partial remission or a minimum of stable disease/no progressive disease for 12 weeks based on disease-specific assessment criteria. This endpoint will be evaluated at 12 months and EoT. 5. Duration of response, defined as the time from the initial occurrence of a documented PR/partial remission or CR until documented disease progression or death due to any cause, whichever occurs first, according to disease-specific assessment criteria. This endpoint will be evaluated at 12 months and EoT. 6. Duration of complete response, defined as the time from the initial occurrence of a documented CR until documented disease progression, relapse, or death due to any cause, whichever occurs first, according to disease-specific assessment criteria. This endpoint will be evaluated at 12 months and EoT. 7. Progression-free survival, defined as the time from the date of administration of the first dose of NVG 222 on this tria | — |
Countries
England, United Kingdom
Outcome results
None listed